Proteome-wide Mendelian randomization and colocalization analysis identify therapeutic targets for stroke

Abstract

Background: Stroke is a leading cause of death and disability worldwide, yet its treatment still faces significant challenges. Mendelian randomization (MR) has been widely used to discover new biomarkers and therapeutic targets. This study aimed to identify therapeutic targets for stroke within the plasma proteome range using MR.

Methods: We conducted a two-sample MR study, evaluating the causal relationships between 2,940 plasma proteins from the UK Biobank-Proteome-wide Association Study (UKB-PPP) and stroke, with further validation in 4,907 plasma proteins from Iceland. Subsequently, drug target proteins were determined using Bayesian colocalization, Summary data-based Mendelian randomization (SMR), and protein-protein interaction (PPI) network construction to validate the role of selected disease-associated proteins.

Results: Preliminary MR analysis identified 11 proteins (LPA, FURIN, MST1, FKBPL, SH2B3, MMP12, F11, ITGAV, DDHD2, VSIR and GAS6) significantly associated with stroke or stroke subtypes. Through SMR and colocalization analysis, 4 potential drug target proteins were identified: FURIN as a potential drug target for stroke and any ischemic stroke, F11 as a potential drug target for cardioembolic stroke, DDHD2 and VSIR as potential drug targets for small vessel stroke. It is worth noting that F11 is currently being used in the development of multiple drugs, FURIN is not only associated with stroke but also appears to have abnormal expression in several cardiovascular diseases. Although research on DDHD2 and VSIR in the context of stroke is relatively limited, current findings indicate that DDHD2 is related to synaptic plasticity, while VSIR is associated with microglia and immune responses.

Conclusion: This study found that the plasma proteins FURIN, F11, DDHD2, and VSIR show promise as potential therapeutic targets for stroke and its subtypes, providing genetic evidence to support precision drug development and insights into the underlying pathological mechanisms of stroke.

Clinical trial number: Not applicable.

Keywords: Drug targets; Ischemic stroke; Mendelian randomization; Plasma proteins; Stroke.

Fig. 1

The design diagram of this study, including the sources of exposure and outcome, threshold parameters, and the workflow of the study

Fig. 2

Volcano plot of plasma proteins with significant causal relationship with stroke identified in the preliminary MR analysis (UKB-PPP, P_fdr < 0.05). Volcano plot a: Stroke (Finland), Volcano plot b: Stroke (MEGASTROKE), Volcano plot c: Ischemic stroke, Volcano plot d: Cardioembolic stroke, Volcano plot e: Large artery stroke, Volcano plot f: Small vessel stroke

Fig. 3

Forest plot of plasma proteins with significant causal relationship with stroke identified in the preliminary MR analysis (UKB-PPP, P_fdr < 0.05)

Fig. 4

Volcano plot of plasma proteins with significant causal relationship with stroke identified in the preliminary MR analysis (deCODE data, P_fdr < 0.05). Volcano plot g: Stroke (MEGASTROKE), Volcano plot h: Ischemic stroke, Volcano plot i: Cardioembolic stroke, Volcano plot j: Large artery stroke

Fig. 5

Forest plot of plasma proteins with significant causal relationship with stroke identified in the preliminary MR analysis (deCODE data, P_fdr < 0.05)

Fig. 6

Colocalization plot of plasma proteins with stroke phenotypes in the preliminary MR analysis results (PPH4>0.8). Colocalization plot a: FURIN-Stroke; Colocalization plot b: FURIN-IS; Colocalization plot c: F11-Cardioembolic stroke; Colocalization plot d: DDHD2 -Small vessel stroke; Colocalization plot e: VSIR-Small vessel stroke

Fig. 7

PPI Network diagram of the interplay between plasma proteins in the results of the preliminary MR analysis